Tropanylhydrazines



A United States Patent 3,132,148 TROPLHYDRAZINES Floyd E. Anderson,Morris Plains, and Metro Fedorchuk, East Orange, Nulz, assignorstoWallace & Tiernan Inc., Belleville, NJ., a corporation of Delaware V aNo Drawing. Filed Mar. 12, 1962, Ser. No. 179,233

7 Claims. (0. 260-492) The invention relates to tropanylhydrazines,sometimes called tropylhydrazines. More particularly the invention isconcerned with novel substituted diaryltropanylhydrazineswhich areuseful as anticholinergic agents. It is also concerned withthe use ofsuch novel diaryltropanylhydrazine compounds, and with therapeuticcompositions containing them. i

According to the present invention there are provided novel'tropanylhydrazine compounds of the formula:

V t Where R represents hydrogen; lower alkyl such as methyl,

ethyl, propyl and butyl; hydroxyloweralkyl; and aralkyl groups such asbenzyl, phenylethyl and phenylpropyl; X represents hydrogen; lower alkyland lower aliphatic acyl such as acetyl, propionyl; and Y and Yrepresent hydrodiphenyl N'-3-tropanylidenehydrazine oxalate( tropinone Idiphenylhydrazone oxalate), compounds where R is CH X is hydrogen, and Yis hydrogen and Y" is Cl, OCH and CH a compound where R is CH CH OH, andX,

' 'Y and Y are all hydrogen, and a compound where R is CH ,.Y and Y bothhydrogen, andX is COCH Acid addition salts and quaternary ammonium saltsof v the tropanylhydrazines are included within this invention.

.By reacting the hydrazine derivativewith a mineral or 'organicacid anaddition salt is produced. Acids such as hydrochloric, sulfuric, formic,acetic, citric, oxalic, maleic,

fumaric, phosphoric, sulphonic cation exchange resins,

carboxylic acid cation exchange resins, and phosphonic cation exchangeresins may be used to form salts.

( Quaternary ammonium salts are readily produced by combining thehydrazine with a suitable alkylating agent such as an alkyl or aralkylester of an acid and particularly dimethyl sulfate, methyl chloride,ethyl bromide, methyl iodide, phenylethyl chloride, benzyl chloride,O-chlorobenzyl bromide and equivalents thereof.

The following examples are presented to illustrate, but

notto limit, the invention.

EXAMPLE 1 N,N-Diphenyl-N-3-Tropanylidenehydrazine Oxalate A solution of1.00 g. (0.007 2 mole) of tropinone, 1.32 g. (0.0072 mole) of1,1-diphenylhydrazine and 10 drops of glacial acetic acid in 10 cc. ofabsolute ethanol was refluxed for 5 hours and then allowed to standovernight. The ethanol was removed by evaporaton on a steam bath,

'dium hydroxide.

3,132,148 Patented May 5, 1964 ice taken up in absolute ethanol and thesolution treated with an excess of an ethanolic solution of oxalic acid.The oxalic acid addition salt was precipitated by the addition of etheryielding a gummy product that solidified on rubbing; yield 0.8 'g. (28%After three recrystallizations from absolute ethanol the light yellowcrystals melted at C. (dec.).

Analysis:

I o n i l N Calculated for CzuHzaNa-CzHzOi 66. 82 6.37 10. 63 Found 66.32 6.21 10. 77, 10. 46

Reaction between 1, 1-diphenylhydrazine and tropinone was also etlectedby heating at 100 C. under reduced pressure in the absence of solventand acid catalyst. The same compound was also obtained when1,1-diphenylhydrazine hydrochloride was reacted withtropinone in ethanolin the presence of sodium-acetate. :Whenthe reaciton between thehydrazine and tropinone was carried 7 out in ethanol in the presence ofglacial acetic acid the yields wereimproved by simultaneously removingthe water formed. .This was conveniently effected by using a Soxhletextractor charged with calcium oxide.

EXAMPLE 2 N ,N -Diphenyl-N '-3-T ropanylhydrazine Oxalate An aqueoussolution of 2.16 g. (0.0055 mole) of N,N- diphenyl-Nf-B-tropanyliclenehydrazine oxalate was made strongly basic with 25%aqueous sodium hydroxide. The oily base was extracted with severalportions of etherand the combined ethereal extracts dried withanhydrousmagnesium sulfate. The dried ethereal solution ofN,N-dipheny1-N'-3 tropanylidenehydrazine was slowly added to 0.5 g.(0.0131 mole) of lithium aluminum hydride in 50 cc. of dry ether. Themixture was stirred and refluxed 'under nitrogen for 24 hours and thecomplex decomposed by the addition of water followed by 25% aqueous so-The water layer was separated and washed twice with ether. The combinedethereal phases were dried with anhydrous magnesium sulfate and theether removed under reduced pressure. The semisolid residue was taken upin anhydrous ethanol and the resulting solution treated with an excessof an ethanolic solution of oxalic acid. The oxalate precipitated as anoil on addition of ether. After rubbing several times with freshportions of ether a semisolid was obtained. This was dissolved inabsolute ethanol and ether added until crystals begin to form; yield0.75 g. (35% After three recrystallizations from absolute ethanol thecream-colored crystals melted at -188" C. (dec.).

Analysis: 1

Calculated for CzoHzsNa-CzHzOi 66.46 6.85 10.57 Found 66.72 6.90 110.43

EXAMPLE 3 l N ,N-Diphenyl-N -3 -T ropanylhydrazine A dry etherealsolution of 3.85 g. (0.0126 mole) of N,N-

d-iphenyl-N'-3-tnopanylidenehydrazine was added slowly to 1.2 g. (0.0315mole) of lithium aluminum hydride in 80 cc. of dry ether. The mixturewas stirred and refluxed unthe oily residue taken up in ether andfiltered. The Y ethereal solution was evaporated to dryness, the residueThe solid was filtered oif and washed with ether.

der nitrogen for 24 hours andthe complex decomposed by the successiveaddition of :1.5 cc. of water, *1.5 cc. of 15% aqueous sodium hydroxideand 7.0 cc. of water. The ethereal phases were combined and dried withanhydrous magnesium sulfate and the ether removed under reducedpressure. The waxy residue was recrystallized from nhexane to yield 2.04g. 3 of product, M.P. '115-1'17.'5

C. A sample for analysis was recrystallizedthree more times fromn-hexane to yield colorless crystals, M.P. 119- Analysis:

l G l H Calculated for CzuHz5N3 -78.13 8.20 Folm g 78.68' 8.19

EXAMPLE 4 N, N-Diphenyl-N'-3-Tr0pany.lhydrazine Methipdide Five grams(0.0163 mole) of N,N-diphenyl-N'-3- tropanylhydrazine was dissolved inacetone and 3.45 g. (an excess) of methyl iodide was added to theresulting solution. The white crystalline product formed almost im--mediately, yielding "6.7 g. (92%); M.P. 240-245 C. (dec.).

The methiodide was recrystallizedonce from methanol,

yield 5.7 g.; -M.P. 243-245 C. (dec.).

Analysis:

| C H I N Calculated for CziHzsINs 56. 11 0. 28 28. 24 9. 35 Found 55.56 6. 55 28. 28 8. 98 28. 32 9. 18

EXAMPLE 5 Be'nzylchloride of N,N-Diphenyl-N'-3-Tropanylhydrazine To asolution of 4.0 g. (0.013 mole) of N,N-diph'enyl- N'-3-tropanylhydrazinein 50 ml. of acetone was added 2.25 ml. (50% in excess) ofbenzylchloride. The resulting mixture was allowed to stand for 4 daysduring which time crystals appeared. The mixture was then refluxed 4hours, cooled, and the white salt filtered to yield 5.0 g., M.P.236-2385 C. (dec.). After two recrystallizations from absolute methanolthe product melted at 160-165 C. The high melting salt dissolved readilyin methanol at room temperature, but on several minutes standingcrystals begin to form. This observation, the decrease in melting pointafter recrystallization and the fact that the melt .resolidifies anddecomposes at 230 C. indicates that the N -p-M ethoxy phenyl-N-Phenylhydrazine To 10.7 g. (0.047 mole) of N-nitroso-p-methoxydiphen=ylamine in 250 ml. of dry ether at C. was slowly added 2.0 g. (0.0525mole) of lithium aluminum hydride in 50 m1. of dry ether. The reactionmixture was stirred an additional hour at 10 C. The complex was thendecomposed with successive additions of 2.0 ml. of water, 2.0 ml. ofaqueous sodium hydroxide, and 6.0 ml. of water while maintaining thetemperature at 10 C. After one hour the reaction mixture was filtered,and the ethereal solution dried over anhydrous magnesium sulfate. Theether was then removed under reduced pressure to 'yield 10.1 g. of acrystalline residue, M.P. 70-73" C.

After three recrystallizations from a mixture of n-hexane 'and ethanol(50:1), the cream colored flakes melted at 71- '72" C. Y

Found Analysis:

Calculated for C13H14N2O 72.87 6.59 13.08 Found 1 73. 75 6. 77 13. 10

The product reduced Fehlings solution on heating, and gave an immediateviolet color in concentrated sulfuric acid.

EXAMPLE 7 N-p-Methoxyphenyl-N-Phenyl-N'-3- T ropanylidenehydrazine Amixture of 7.5 g. (0.054 mole) of tropinone, 11.5 g. (0.054 mole) ofNap-methoxyphenyl-Nphenylhydrazine,

.one ml. of glacial acetic acid and ml. of absolute ethanol was refluxedfor 6 /2 hours. Water produced by the reaction was removed by causingthe refluxing solvent to return through a Sohlet extnactor filled withcalcium oxide. Forty percent aqueous sodium hydroxide (1.75 ml.) wasadded to the reaction mixture and the resulting solution evaporated todryness under reduced pressure. The residue was taken up in ether andfiltered; the ethereal filtrate was washed with water until the waterwashings tested near neutral; it was then dried over anhydrous magnesiumsulfate. The drying agent was removed and the ethereal solutionconcentrated and chilled in the refrigerator. The tan-coloredcrystalline hydrazone which separated weighed 12.0 g., M.P. 66-71. C.The crude hydrazone was dissolved in hot isopropyl ether and thesolution treated with four successive portions of charcoal. Theresulting solution yielded colorless crystals. After three additionalrecrystallizations from isopropyl ether, the product melted at 66-72 C.

Analysis:

Calculated 1dr CmHuNaO EXAMPLE 8 I N -p-M ethoxyphenyl-N -Phenyl-N'-3-Tropanylhydrazine A suspension of 3.76 g. (0.011 mole) of crudeN-pmethoxyphenyl-N-phenyl-N'-3-tropanylidenehydrazine in .50 ml. of dryether was added to 1.3. g- (0.033 mole) of lithium aluminum hydride in.100 ml. of dry ether. The mixture was refluxed with stirring for 24hours. The

.lithium aluminum hydride complex was then decomposed "by the successiveaddition of 0.3 ml. of water, 1.3 ml. of 1 15% aqueous sodium hydroxide,and 3.9' ml. of water. l The mixture was filtered and the etherealsolution dried 1 over anhydrous magnesium sulfate. The ether was thenremoved yielding an oil which crystallized on standing.

This was triturated with isopropyl ether and filtered to obtain 2.5 g.of a colorless solid. After four recrystallizations from isopropylether, the colorless needles melted at 132.5-133.5 C.

EXAMPLE 9 N-p-Chlorophenyl-N-Phenylhydrazine Oxalate To 5 .7 .g. (0.0245mole) of N -nitroso-p-chlorodiphenylamine in 75 m1. of dry other at 10C. was slowly added 1.05 g. (0.0275 mole) of lithium aluminum hydride in25 ml. of dry ether. The reaction mixture was stirred an additional hourat 10 C. The complex was then drazines of Biel, U.S. Patent 2,927,1 1 1,but there are also ethereal solution dried over anhydrous magnesium sul-$1 basic "difierencesin the pharmacological activities. Thesedifferences have been demonstrated, as shown in the accompanying Table Awherein I represents the N,N-di-" phenyl-N'-3 tropanylhydrazine of thisinvention and II fate and then treated with an excess of an etherealsolution of anhydrous oxalic acid. Yield of the crude oxalate was 6.7 g.(89%). A portion of the crude material was recrystallized once fromabsolute ethanol-to yield a white powdery oxalate, M.P. -148-9 C.-(dec.).

The above oxalate proved to be identical with that prepared from thehydrazine synthesized by the method of M. Jamison and E. Turner, Journalof the Chemical Society (London), p. 1954 (1937).

Analysis:

Caleulatedfor omnnorNl-ozmol. 9.08 11.48 F t 9.1 11.08

7 EXAMPLE 10 N p-Ch l orophenyl-N -Pheny l-N -3-Tropany lhy drazine' Amixture of 8.2 g. (0.059 mole) of tropinone, 12.9 g. (0.059 mole) ofN-p-chlorophenyl-N-phenylhydnazine, one ml. of glacial acetic acid, and125 ml. ofabsolute ethanol was refluxed for 7 hours. Water produced bythe reaction was removed by causing the refluxing solvent to returnthrough a Soxhlet extractor filled with calcium oxide. After theaddition of 1.75 ml. of aqueous sodium hydroxide, the ethanol wasremoved under reduced pressure. The residue was taken up in ether,filtered, and

, the ethereal solution washed with water until the washings tested nearneutral. The ethereal solution was then dried over anhydrous magnesiumsulfate. Addition of an ethereal solution of anhydrous, oxalic acidyielded a gummy oxalate which solidified on tritunation. This oxalate,tropinone N-p-chlorophenyl-N-phenylhydrazone oxalate, did

7 not give a blue color when dissolved in concentrated sulfuric acid, areaction characteristic of di-arylhydrazines. The crude oxalate wasdissolved in water, the solution made strongly basic with sodiumhydroxide, and the tree base taken up in ether and dried over anhydrousmagnesium sulfate.

The dried ethereal solution of the hydrazone was added to 6.7 g. (0.177mole) of lithium aluminum hydride in 400 ml. of dry ether. The mixturewas refluxed with stirring for 23 hours. The complex wasthen decomposedby the successive additions of 6.7 of water, 6.7 ml. of 15% aqueoussodium hydroxide, and 20.1 ml. of water. The mixture was filtered andthe ethereal solution dried over anhydrous magnesium sulfate. The etherwas then removed under reduced pressure yielding a brown oil. Thisviscous oil was redissolved in ether and the ether again evaporated on aWater bath. 'As the solution became more concentrated the productcrystallized. The

crystalline mass was triturated with isopropyl ether and filtered toyield 6.0 g. of a white solid, M.P. 112-117 C. After threerecrystallization from isopropyl ether, the colorless needles melted at117-118 C. This compound gave a blue color, when dissolved inconcentrated sulfuric acid. i 7

Analysis:

o H N GalculatedmrCmHnCINa 70.26 7.07 12.28 Found 70. 31 7.26 12. 13

represents. the N-rnonophenyl =N 3 tropanylhydrazine compoundof the BielUS. Patent 2,927,111. 3

TABLE A Spontaneous Gut Motility Anti-Tre- Com- Antispasmodie moriuepound Activity Activity Dog I Rat I Markedly Markedly 2-10XAtro- Marked.

' I Inhibited. Inhibited. pine i p A a potency. II- Little at- Not at1/300 of Atro- None.

iected; Less fected. pine tlfuin 1/40 potency. o

The results shown in the above table can be better understood by thefollowing explanation:

Spontaneous gut motility.-Antispasmodic agents characteristicallyinhibit intestinal motility as indicated (a) by reduction in the lengthof time required for passage of a test (charcoal) mealin the rat; and,(b) by reduction in the magnitude and/ or frequency of intestinalcontractions inthe dog. As shown in the table the diphenyl derivative(1) markedly inhibited this effect in the rat and dog. t'Biels compound,however, was almost completely devoid of such activity. To demonstratesuch activity 40 times as much of the Biel compound was required.

Antispasmodic activity.-Antispasmodic compounds characteristicallyinhibit spasms of the intestine. that are induced by chemical agentssuch as acetylchloline; In

- e.g.,' benztropine methanesulfonate (Cogentin), ethopropazine(Parsidol) atropine, etc., inhibit the tremor-producing effects of theagent Tremorine which is 1,4-dipyrrolidino-2-butyne. There is evidencethat such activity in animals is correlated with the compoundstherapeutic effectiveness in hyperkinetic states, such as park-insonism(paralysis agitans), chorea, etc. The diphenyl'derivative (I) exhibitedanti-Tremorine activity in the potency range of Cogentin, which iscustomarily employed as a standard of reference. The ED of I wasactually 6.9 (4.2 11.4) mg./kg., p.o., or approximately /32 of thelethal dose, indicating a wide margin of safety. This ED is the oraldose which is effective in fifty percent of the animals (calculatedaccording to the method of J. T. Litchfield, Jr.,

The compounds of this invention are useful as anti- 2 cholinergic orantispasmodic agents. They are not only diiferent chemically from themonophenyltropanyl byand F. W. Wilcoxon, Journal of Pharmacology andExperimental Therapeutics, vol. 96,page 99 (1949)). The Biel compound,however, was completely devoid of such activity. 1 V

The compounds of this invention are useful by themselves asanticholinergic agents, but generally are mixed with pharmaceuticallyacceptable carriers, which may be present in wide limits such as 1% toof the total composition.

The following formulationsare suitable generally for use in dogs, catsand other mammals, and dosage amounts for humans are included. Theamount of drug compound as drug base in a unit dose for a human cansuitably range from approximately .1 mg.'to 10.0 mg. These formulationsmay utilize any of the compounds of the general formula, and mostparticularly with N,N-diphenyl-N'-3-tropanylhydrazine and its non-toxicsalts. This compound appears to have an activity in the range of 2 to1-0 times that of atropine. In addition to the anticholinergic activityand anti-tremorine activity of these compounds the quaternary ammoniumderivatives exhibit Considerable gastric anti-secretory action in theamounts indicated. For purposes of brevity in these formulae thecompound N,N-diphenyl-N'-3-tropanylhydrazine is referred to as the Drug.

(1) Formula for 1 Liter of Eye Drop Preparation V Range Drug, as solublehydrochloride, citrate, acetate or phosphate salt g 2 to 10 Benzalkoniumchloride mg 20 to 40 NaH PO g 4.5 Na HPO g NaCl approx. g 1 4.5 Steriledistilled water to make 1 liter.

1 Slight variations in the amount of NaCl are made contingent on thelevel required to produce an isotonic solution.

An isotonic solution is considered to be a solution having a freezingpoint of 0.52 C.

A solution of the above components is prepared accord ing to the art,subjected to sterile filtration and packaged aseptically intoappropriate sterile containers;

(2) Ophthalmic Ointment, 1 Kilo Range Drug,'as soluble hydrochloride,citrate, acetate or phosphate g Water for injection (suificient todissolve Drug) mL; 10 to 50 Anhydrous lanolin g 100 Yellow petrolaturnto make 1 kilo.

The ointment is prepared according to the art, being certain that all ofthe Drug has dissolved in the water for injection before admixing withthe ointment components. This is necessary to insure elimination of anyparticulate matter. The product is then sterilized and packagedaseptically into sterile tubes.. An appropriate preservative such as1:25,0 benzalkonium chloride can be added.

(3) Injectable Form, 1 Liter I Range Drug, as soluble hydrochloride,citrate,

acetate or phosphate salt mg 1-00 to 10,000 Methylparaben g Water forinjection to make 1 liter.

A solution is prepared according to the art, subjected to sterilefiltration, and then packaged aseptically into sterile ampules. 10 mg.of Drug.

(4) Topical Ointment Range Drug, as soluble hydrochloride, citrate,acetate or phosphate salt g Distilled water (sufiicient to dissolveDrug) ml 10 to 50 Anhydrous lanolin g 100 White wax g Q. 50 Petrolatumto make 1 kilo.

The Drug is dissolved in suificient water to efiect solution. Theanhydrous lanolin, white wax and petrolatnm are melted and blended untiluniform. The drug solution is introduced into the melt at a temperaturenot in excess of 40 C, The mixture is then stirred until congealed andpackaged in appropriate tubes or jars.

(5) Oral Forms (a) Capsules-1 kilo mix divided into 5,000 capsules:

Range, g. Drug, as soluble hydrochloride, citrate, acetate or phosphatesalt 1 to 5 0 Magnesium stearate 5 Excipient (lactose, dicalciumphosphate or starch) to make 1 kilo.

A 1 ml. quantity would containfrom 0.1 to

8 The Drug is blended-"with magnesium stearate and excipient until auniform mixture results. This powder blend is then subdivided into 5,000capsules of appropriate size; The composition per capsule would be:

1 Range, mg. Drug 0.2 to 10 Magnesium stearate 1 Excipients to make 200mg.

(b),Tablets1 kilo mix divided into 4,000 tablets:

' Range, g.

-Drug, as soluble hydrochloride, citrate, acetate or phosphate salt 0.8to 40 Lactose 700 'Starch 200 Drug m 0.2 to 10 Vehicle to make ml 5 (d)Elixir-1 liter: Range Drug as soluble hydrochloride, citrate, acetate orphosphate salt mg 40 to 2000 Glycerin I g 50 1 Sucrose g 300 1 Alcoholml 200 Methylparaben g 1.5

is dissolved in distilled water.

'tilled water. Each 5 ml. teaspoonful of this mixture con .Prepare. auniform mix and then granulate with a starch paste prepared by mixing 1pound of starch in sufficient boiling distilled water to make 1 gallon.

Dry granules, reduce to appropriate mesh size (10 to 20 mesh) and add:

Magnesium stearate g 10 Starch to make 1 kilo.

Mix until uniform and then compress on appropriate tablet machine. Eachtablet should weigh 250 mg. The composition per tablet ,would be:

Flavor and color (as required).

Distilled water to make 1 liter.

The methyl and propylparabens are dissolved in hot distilled water. Cornsyrup and sugar are then added.

Drug, color and flavor are added at room temperature and the finalvolume is adjusted to 1 liter. Each 5 m1.

teaspoonful of thismixture contains:

Flavor and color (as required). Distilled water to make 1 liter.

The methylparaben is dissolved in the alcohol. The Drug Other componentsare added at room temperature and stirred until completely in solution.Final volume is adjusted to 1 liter with dis- 'tains:

. Range 1 'Drug mg 0.2 to 10 Vehicle to make ml 5 (a) Suspension-1liter:

Range Drug, as base or insoluble salt such as oxalate,

palmitate or mandelateu mg 40 to 2000 Methylparaben gr 1.5 Propylparaben3 'g 0.5 Methyl'cellulose, 400 cps g 20 Sodium Sucaryl g 10 Glycerin 50Flavor and color (as required). Distilled Water to make 1 liter.

The methyl cellulose is first mixed with the glycerin to facilitateWetting. About half the distilled water is added and allowed to standovernight. Methyl and propylparaben are dissolved in hot distilledwater, blended with the Wetted methyl cellulose and mixed well. Drug,sodium Sucaryl, flavor and color are added with mixing and the finalvolume adjusted to 1 liter with distilled Water. The entire product isthen passed through a colloid mill at minimal setting, or through ahomogenizer to insure permanent dispersion of the insoluble Drug. Each 5ml. teaspoonful of this product contains:

Range Drug me 0.2'to Suspension vehicle to make ml 5 Various changes andmodifications of the invention can be made, and to the extent that suchvariations incorporate the spirit of this invention, they are intendedto be included within the scope of the appended claims.

We claim: i

1. A therapeutic compound of the class consisting of a free base, itsaddition salts with non-toxic acids, lower alkyl quaternary ammoniumsalts and phenyl-lower-alkyl it? quaternary ammonium salts, said freebase having the formula:

where R represents a member of the group consisting of hydrogen, loweralkyl, hydroxy lower alkyl, and phenyl substituted lower alkyl; Xrepresents a member of the group consisting of hydrogen, lower alkyl,lower alkanoyl and Y and Y represent a member of the group consisting ofhydrogen, halogen, lower alkyl, and lower alkoxy.

2. N,N-dipheny1-N-3-tropanylhydrazine.

3. The non-toxic acid addition salt of the compound of claim 2.

4. The oxalic acid addition salt of the compound of claim 2.

1. A THERAPEUTIC COMPOUND OF THE CLASS CONSISTING OF A FREE BASE, ITS ADDITION SALTS WITH NON-TOXIC ACIDS, LOWER ALKYL QUATERNARY AMMONIUM SALTS AND PHENYL-LOWER-ALKYL QUATERNARY AMMONIUM SALTS, SAID FREE BASE HAVING THE FORMULA: 